An inhibitor cystine knot (aka ICK or Knottin) is a protein structural motif containing three disulfide bridges. Knottins are one of three folds in the cystine knot motif; the other closely related knots are the Growth Factor Cystine Knot (GFCK) and the Cyclic Cystine Knot (CCK; cyclotide).[2] Types include a) cyclic mobius, b) cyclic bracelet, c) acyclic inhibitor knottins.[3] Cystine knot motifs are found frequently in nature in a plethora of plants, animals, and fungi and serve diverse functions from appetite suppression to anti-fungal activity.[4]
Top: general schematic of the structure of a knottin. A macrocyclic knot is formed by the core of beta strands (arrows) and disulfide bonds (yellow connections between numbered cysteines). Knottins are differentiated from GFCKs by the connectivity of their cysteines. Bottom: The general structure is easily seen in this crystal structure of EETI II taken from the protein database (PDB: 2IT7).
MCh-1: A plant inhibitor cystine knot peptide from Momordica charantia. PDB entry 2m2q.[1]
Along with the sections of polypeptide between them, two disulfides form a loop through which the third disulfide bond (linking the 3rd and 6th cysteine in the sequence) passes, forming a knot. The motif is common in invertebrate toxins such as those from arachnids and molluscs. The motif is also found in some inhibitor proteins found in plants, but the plant and animal motifs are thought to be a product of convergent evolution.[5] The ICK motif is a very stable protein structure which is resistant to heat denaturation and proteolysis.[6] CK peptide components of venoms target voltage-gated ion channels but members of the family also act as antibacterial and haemolytic agents.[7] Plant ICK proteins are often protease inhibitors.
Knottins have high stability to pH, heat, and enzymes. Because of their stability and their favorable pharmacodynamic properties, knottins are becoming increasingly popular as protein engineering scaffolds. Moreover, engineered knottins have shown significant promise as therapeutics, imaging agents, and targeting agents for chemotherapy.[8]
The mammalian proteins Agouti signalling peptide and Agouti related peptide are the only known mammalian examples of this motif. Both are neuropeptides involved in cell signalling. The former is responsible for hair (fur) colouration.
The motif is similar to the cyclic cystine knot or cyclotide, but lacks the cyclisation of the polypeptide backbone which is present in the latter family. The growth factor cystine knot (GFCK) shares the motif but its topology is such that it is the bond between the first and fourth disulfide which threads through the loop.
^He, W. J.; Chan, L. Y.; Clark, R. J.; Tang, J.; Zeng, G. Z.; Franco, O. L.; Cantacessi, C.; Craik, D. J.; Daly, N. L.; Tan, N. H. (2013). Driscoll, Paul C (ed.). "Novel Inhibitor Cystine Knot Peptides from Momordica charantia". PLOS ONE. 8 (10): e75334. Bibcode:2013PLoSO...875334H. doi:10.1371/journal.pone.0075334. PMC3792974. PMID 24116036.
^. Cyclotide.com. Archived from the original on 2015-02-05. Retrieved 2018-03-13.
^Zhu, S.; Darbon, H.; Dyason, K.; Verdonck, F.; Tytgat, J. (2003). "Evolutionary origin of inhibitor cystine knot peptides". The FASEB Journal. 17 (12): 1765–1767. doi:10.1096/fj.02-1044fje. PMID 12958203. S2CID 1117887.
^Daly, N. L.; Craik, D. J. (2011). "Bioactive cystine knot proteins". Current Opinion in Chemical Biology. 15 (3): 362–368. doi:10.1016/j.cbpa.2011.02.008. PMID 21362584.
^Craik, D. J.; Daly, N. L.; Waine, C. (2001). "The cystine knot motif in toxins and implications for drug design". Toxicon. 39 (1): 43–60. doi:10.1016/S0041-0101(00)00160-4. PMID 10936622.
^Kintzing, James R; Cochran, Jennifer R (2016). "Engineered knottin peptides as diagnostics, therapeutics, and drug delivery vehicles". Current Opinion in Chemical Biology. 34: 143–150. doi:10.1016/j.cbpa.2016.08.022. PMID 27642714.
External links
The KNOTTIN Database
March 01, 2023
inhibitor, cystine, knot, inhibitor, cystine, knot, knottin, protein, structural, motif, containing, three, disulfide, bridges, knottins, three, folds, cystine, knot, motif, other, closely, related, knots, growth, factor, cystine, knot, gfck, cyclic, cystine, . An inhibitor cystine knot aka ICK or Knottin is a protein structural motif containing three disulfide bridges Knottins are one of three folds in the cystine knot motif the other closely related knots are the Growth Factor Cystine Knot GFCK and the Cyclic Cystine Knot CCK cyclotide 2 Types include a cyclic mobius b cyclic bracelet c acyclic inhibitor knottins 3 Cystine knot motifs are found frequently in nature in a plethora of plants animals and fungi and serve diverse functions from appetite suppression to anti fungal activity 4 Top general schematic of the structure of a knottin A macrocyclic knot is formed by the core of beta strands arrows and disulfide bonds yellow connections between numbered cysteines Knottins are differentiated from GFCKs by the connectivity of their cysteines Bottom The general structure is easily seen in this crystal structure of EETI II taken from the protein database PDB 2IT7 MCh 1 A plant inhibitor cystine knot peptide from Momordica charantia PDB entry 2m2q 1 Along with the sections of polypeptide between them two disulfides form a loop through which the third disulfide bond linking the 3rd and 6th cysteine in the sequence passes forming a knot The motif is common in invertebrate toxins such as those from arachnids and molluscs The motif is also found in some inhibitor proteins found in plants but the plant and animal motifs are thought to be a product of convergent evolution 5 The ICK motif is a very stable protein structure which is resistant to heat denaturation and proteolysis 6 CK peptide components of venoms target voltage gated ion channels but members of the family also act as antibacterial and haemolytic agents 7 Plant ICK proteins are often protease inhibitors Knottins have high stability to pH heat and enzymes Because of their stability and their favorable pharmacodynamic properties knottins are becoming increasingly popular as protein engineering scaffolds Moreover engineered knottins have shown significant promise as therapeutics imaging agents and targeting agents for chemotherapy 8 The mammalian proteins Agouti signalling peptide and Agouti related peptide are the only known mammalian examples of this motif Both are neuropeptides involved in cell signalling The former is responsible for hair fur colouration The motif is similar to the cyclic cystine knot or cyclotide but lacks the cyclisation of the polypeptide backbone which is present in the latter family The growth factor cystine knot GFCK shares the motif but its topology is such that it is the bond between the first and fourth disulfide which threads through the loop Proteins which contain the ICK motif EditAgouti related peptide Agouti signalling peptide Albumin I Covalitoxin II DkTx Grammotoxin GsMTx 4 Guangxitoxin Hainantoxin Hanatoxin Heteroscodratoxin 1 Huwentoxin Maurocalcine Theraphosa leblondi toxin d Palutoxin Phrixotoxin Psalmotoxin Robustoxin Stromatoxin Tachystatin Vanillotoxin VejocalcinReferences Edit He W J Chan L Y Clark R J Tang J Zeng G Z Franco O L Cantacessi C Craik D J Daly N L Tan N H 2013 Driscoll Paul C ed Novel Inhibitor Cystine Knot Peptides from Momordica charantia PLOS ONE 8 10 e75334 Bibcode 2013PLoSO 875334H doi 10 1371 journal pone 0075334 PMC 3792974 PMID 24116036 Knots Cyclotide com Archived from the original on 2015 02 05 Retrieved 2018 03 13 Reinwarth Molecules 17 12533 2012 http www mdpi com 1420 3049 17 11 12533 htm Zhu Shunyi Darbon Herve Dyason Karin Verdonck Fons Tytgat Jan September 2003 Evolutionary origin of inhibitor cystine knot peptides FASEB Journal 17 12 1765 1767 doi 10 1096 fj 02 1044fje ISSN 1530 6860 PMID 12958203 S2CID 1117887 Zhu S Darbon H Dyason K Verdonck F Tytgat J 2003 Evolutionary origin of inhibitor cystine knot peptides The FASEB Journal 17 12 1765 1767 doi 10 1096 fj 02 1044fje PMID 12958203 S2CID 1117887 Daly N L Craik D J 2011 Bioactive cystine knot proteins Current Opinion in Chemical Biology 15 3 362 368 doi 10 1016 j cbpa 2011 02 008 PMID 21362584 Craik D J Daly N L Waine C 2001 The cystine knot motif in toxins and implications for drug design Toxicon 39 1 43 60 doi 10 1016 S0041 0101 00 00160 4 PMID 10936622 Kintzing James R Cochran Jennifer R 2016 Engineered knottin peptides as diagnostics therapeutics and drug delivery vehicles Current Opinion in Chemical Biology 34 143 150 doi 10 1016 j cbpa 2016 08 022 PMID 27642714 External links EditThe cyclotide webpage The KNOTTIN Database Retrieved from https en wikipedia org w index php title Inhibitor cystine knot amp oldid 1121649006, wikipedia, wiki, book, books, library,
